Epidermis system coefficients

Epidermis consists of the stratum comeum and adjacmt viable layer. The system coefficimts of the epidermis can be obtained by measuring the permeation coefficient of the probe compounds in the donor solution of the chranical mixtures using static Franz and flow-through diffusion cells. The log k value of a given probe compound is scaled to the solute descriptors of the compound via the LFER equation (Equation 5.1, where log SP = log k ). A LFER equation matrix is genraated from the permeation coefficients and the solute descriptors of all the probe compounds (Equation 5.2). The system coefficients of the epidermis and the ehemieal mixture can be obtained by multiple linear regression analysis of the LFER equation matrix Pog kp, R, Jt, a, p, V]. The system coefficients of the epidomis would be different from... 

It is noted that the system coefficients are not the properties of the epidermis itself rather, they are properties of the absorption system composed of the epidermis and the medium of the chemical mixture. Only an absorption system has specific permeation properties that can be measured quantitatively by the system coefficients. This situation is also appfied to the permeabifity measurement, that is, a given permeabihty of a chemical is for a specific absorption system consisting of the epidermis and the medium of the donor solution. The permeation coefficients of chemicals caimot simply be compared if they are measured in different media (e.g., water vs. ethanol). At a given dose concentration, different media could provide a significantly different driving force for the passive diffusion, which governs the absorption processes. 

As the lipophilicity of compounds continues to increase (as estimated by their octanol-water partition coefficients), dermal penetration does not increase indefinitely. In fact, it is limited by a number of factors. As we have seen above, penetration into the systemic circulation for lipophilic compounds is limited by their very modest capacities to penetrate the aqueous layers of the skin (dermis and viable epidermis), as well as their relative reluctance to enter the bloodstream. These factors set a natural upper limit to the dermal penetration coefficients for very lipophilic compounds of 10 cmh. In many cases, however, it is not the penetration coefficient itself in which we are interested, but rather the flux of a compound through the skin. This flux is the product of a penetration coefficient and a driving concentration. Since the aqueous layers of the skin are the major impediment for lipophilic compounds, solubility in water plays a major role in determining the maximum flux of such compounds through the skin. Like other parameters we have... 

At the other end of the spectrum, however, in transdermal systemic delivery, the molecular attributes required are rather different. In this case, compounds are required to partition into the relatively lipophilic stratum corneum, diffuse rapidly across the stratum corneum and partition easily into the more hydrophilic viable epidermis and dermis prior to vascular removal. The intrinsic requirements of compounds for transdermal delivery are, therefore, a medium polarity (a log octanol-water partition coefficient of 1-3), a low molecular volume and a lack of potential to bind to skin components (e.g., via hydrogen bonding). 

Theoretically, an ideal corticoid should permeate the stratum corneum and reach an adequate concentration in the epidermis without crossing the dermis to reach the systemic circulation. This may be achieved by increasing the lipophilicity of the topically active steroids resulting in an alteration of the partition coefficient. 

---